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Journal articles on the topic 'Androgens'
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1
Calado, Rodrigo T., William T. Yewdell, Keisha L. Wilkerson, Joshua A. Regal, Sachiko Kajigaya, Constantine A. Stratakis, and Neal S. Young. "Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells." Blood 114, no. 11 (September 10, 2009): 2236–43. http://dx.doi.org/10.1182/blood-2008-09-178871.
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Abstract Androgens have been used in the treatment of bone marrow failure syndromes without a clear understanding of their mechanism of action. Blood counts of patients with dyskeratosis congenita or aplastic anemia with mutations in telomerase genes can improve with androgen therapy. Here we observed that exposure in vitro of normal peripheral blood lymphocytes and human bone marrow–derived CD34+ cells to androgens increased telomerase activity, coincident with higher TERT mRNA levels. Cells from patients who were heterozygous for telomerase mutations had low baseline telomerase activity, which was restored to normal levels by exposure to androgens. Estradiol had an effect similar to androgens on TERT gene expression and telomerase enzymatic activity. Tamoxifen abolished the effects of both estradiol and androgens on telomerase function, and letrozole, an aromatase inhibitor, blocked androgen effects on telomerase activity. Conversely, flutamide, an androgen receptor antagonist, did not affect androgen stimulation of telomerase. Down-regulation by siRNA of estrogen receptor-α (ERα), but not ERβ, inhibited estrogen-stimulated telomerase function. Our results provide a mechanism for androgen therapy in bone marrow failure: androgens appear to regulate telomerase expression and activity mainly by aromatization and through ERα. These findings have potential implications for the choice of current androgenic compounds and the development of future agents for clinical use.
2
Oosterhoff, Josien K., J. Anton Grootegoed, and Leen J. Blok. "Expression profiling of androgen-dependent and -independent LNCaP cells: EGF versus androgen signalling." Endocrine-Related Cancer 12, no. 1 (March 2005): 135–48. http://dx.doi.org/10.1677/erc.1.00897.
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Prostate cancer development often includes a shift from androgen-dependent to androgen-independent growth. It is hypothesized that, during this transition, growth factors like the epidermal growth factor (EGF) gain importance as activators of tumour cell proliferation. To study this, androgen- and EGF-regulation of growth and gene-expression was analysed in the androgen-dependent human prostate cancer cell line LNCaP-FGC (FGC) and its androgen-independent derivative line LNCaP-LNO (LNO). It was observed that androgen-dependent FGC cells require exposure to either androgens or EGF to proliferate. This is in contrast to androgen-independent LNO cells that showed significant proliferation in medium depleted of androgens and growth factors. Gene expression data were obtained for the androgen-dependent FGC and androgen-independent LNO cells cultured in the presence or absence of androgens (synthetic R1881) or EGF for different time periods. Expression profiling showed that many cell cycle genes, including a number of androgen- and EGF-regulated genes, are constitutively activated in androgen-independent LNO cells. Furthermore, the overlap between changes in gene expression activated by androgen and EGF receptor signalling pathways was found to be very high (75%). These results partly explain why androgen-independent LNO cells can proliferate in the absence of androgenic stimulation. However, possibly other, so far unknown, signal transduction pathways that induce and maintain proliferation, have also been activated.
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HERAS, MARCELO A. DE LAS, and RICARDO S. CALANDRA. "S‐Adenosyl‐L‐Methionine Decarboxylase Activity in the Rat Epididymis: Ontogeny and Androgenic Control." Journal of Andrology 12, no. 3 (May 6, 1991): 209–13. http://dx.doi.org/10.1002/j.1939-4640.1991.tb00252.x.
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ABSTRACT: The authors describe the occurrence of high levels of S‐adenosyl‐L‐methionine decarboxylase (SAMDC) activity in the rat epididymis, and its ontogeny and androgenic control. As early as 15 days of age, SAMDC activity exists, although a peak of activity is observed at 25 days. Bilateral orchidectomy resulted in a decline of epididymal SAMDC activity. However, an androgen‐independent fraction, accounting for 34% of total activity, appears to exist in the epididymis. In 45‐day‐old orchidectomized rats, SAMDC activity was stimulated by testosterone treatment in a dose‐dependent manner. However, treatment of 45‐day‐old intact animals with a high dose of the androgen failed to modify SAMDC activity, indicating that, at this age, the enzyme is maximally stimulated by endogenous androgens. The observed effect of testosterone on castrated rats was completely abolished by concomitant treatment with the antiandrogen flutamide. This compound was ineffective on the androgen‐insensitive fraction. To assess the contribution of circulating and luminal androgens to the maintenance of epididymal SAMDC, rats were unilaterally orchidectomized and activity was determined in both epididymides after 7 days. The SAMDC activity was identical in epididymides from both sides, suggesting that circulating androgens suffice to maintain normal levels of activity. It was concluded that androgens regulate epididymal SAMDC activity, although an androgen‐independent fraction appears to exist.
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Cunha, Gerald R., Annemarie A. Donjacour, and Yoshiki Sugimura. "Stromal–epithelial interactions and heterogeneity of proliferative activity within the prostate." Biochemistry and Cell Biology 64, no. 6 (June 1, 1986): 608–14. http://dx.doi.org/10.1139/o86-084.
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Growth and functional activity within the prostate gland is known to be regulated by androgens whose effects are thought to be mediated via androgen receptors. This concept has been derived in large part through analysis of whole organ homogenates, an approach which ignores potential heterogeneity of biological activity within the gland and the importance of cell–cell interactions. In this review recent findings are summarized which demonstrate that growth of the prostatic ductal network during prepubertal periods, as well as during prostatic regeneration in androgen-treated adult castrates, is nonuniform, with ductal growth being highest at the ductal tips and much lower in proximal ducts closer to the urethra. Androgen dependency for maintenance of ductal architecture following castration follows a similar pattern in that castration results in total destruction of distal ductal architecture, while proximal ducts are maintained albeit in an atrophic state. Thus, striking differences in biological properties are found in distal versus proximal prostatic ducts. Morphogenesis, growth, and secretory cytodifferentiation within the developing prostate is eleicited by androgens which act via mesenchymal–epithelial interactions. Through analysis of chimeric prostates constructed with androgen-receptor-positive wild-type mesenchyme and androgen-receptor-negative Tfm (testicular feminization) bladder epithelium, it is now evident that androgenic effects can be elicited in androgen-receptor-deficient (androgen-insensitive) Tfm prostatic epithelium, provided that the connective tissue component of the chimeric prostate is wild type. This observation has been made for both the developing and adult prostate. From this data it is evident that certain androgenic effects (ductal morphogenesis, epithelial growth, and secretory cytodifferentiation) do not require the presence of intraepithelial androgen receptors. In fact, recent evidence indicates that the epithelial androgen receptor is neither necessary or sufficient for induction of androgenic effects. Instead, many lines of evidence support the view that epithelial response to androgens is mediated via inductive trophic influences from mesenchymal (stromal) cells which are exceedingly important androgen targets.
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Hoon Lee, Jung, Haibiao Gong, Shaheen Khadem, Yi Lu, Xiang Gao, Song Li, Jian Zhang, and Wen Xie. "Androgen Deprivation by Activating the Liver X Receptor." Endocrinology 149, no. 8 (May 1, 2008): 3778–88. http://dx.doi.org/10.1210/en.2007-1605.
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Prostate cancer is the most commonly diagnosed and the second leading cause of cancer death in men. The androgens-androgen receptor signaling plays an important role in normal prostate development, as well as in prostatic diseases, such as benign hyperplasia and prostate cancer. Accordingly, androgen ablation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel nuclear receptor-mediated mechanism of androgen deprivation. Genetic or pharmacological activation of the liver X receptor (LXR) in vivo lowered androgenic activity by inducing the hydroxysteroid sulfotransferase 2A1, an enzyme essential for the metabolic deactivation of androgens. Activation of LXR also inhibited the expression of steroid sulfatase in the prostate, which may have helped to prevent the local conversion of sulfonated androgens back to active metabolites. Interestingly, LXR also induced the expression of selected testicular androgen synthesizing enzymes. At the physiological level, activation of LXR in mice inhibited androgen-dependent prostate regeneration in castrated mice. Treatment with LXR agonists inhibited androgen-dependent proliferation of prostate cancer cells in a LXR- and sulfotransferase 2A1-dependent manner. In summary, we have revealed a novel function of LXR in androgen homeostasis, an endocrine role distinct to the previously known sterol sensor function of this receptor. LXR may represent a novel therapeutic target for androgen deprivation, and may aid in the treatment and prevention of hormone-dependent prostate cancer.
6
Chen, Jia-Feng, Pei-Wen Lin, Yi-Ru Tsai, Yi-Chien Yang, and Hong-Yo Kang. "Androgens and Androgen Receptor Actions on Bone Health and Disease: From Androgen Deficiency to Androgen Therapy." Cells 8, no. 11 (October 25, 2019): 1318. http://dx.doi.org/10.3390/cells8111318.
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Androgens are not only essential for bone development but for the maintenance of bone mass. Therefore, conditions with androgen deficiency, such as male hypogonadism, androgen-insensitive syndromes, and prostate cancer with androgen deprivation therapy are strongly associated with bone loss and increased fracture risk. Here we summarize the skeletal effects of androgens—androgen receptors (AR) actions based on in vitro and in vivo studies from animals and humans, and discuss bone loss due to androgens/AR deficiency to clarify the molecular basis for the anabolic action of androgens and AR in bone homeostasis and unravel the functions of androgen/AR signaling in healthy and disease states. Moreover, we provide evidence for the skeletal benefits of androgen therapy and elucidate why androgens are more beneficial than male sexual hormones, highlighting their therapeutic potential as osteoanabolic steroids in improving bone fracture repair. Finally, the application of selective androgen receptor modulators may provide new approaches for the treatment of osteoporosis and fractures as well as building stronger bones in diseases dependent on androgens/AR status.
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Culig, Zoran. "Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer." Cancers 13, no. 12 (June 12, 2021): 2944. http://dx.doi.org/10.3390/cancers13122944.
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Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways.
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Smyth, Kendra N., Lydia K. Greene, Tim Clutton-Brock, and Christine M. Drea. "Androgens predict parasitism in female meerkats: a new perspective on a classic trade-off." Biology Letters 12, no. 10 (October 2016): 20160660. http://dx.doi.org/10.1098/rsbl.2016.0660.
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The immunocompetence handicap hypothesis posits that androgens in males can be a ‘double-edged sword’, actively promoting reproductive success, while also negatively impacting health. Because there can be both substantial androgen concentrations in females and significant androgenic variation among them, particularly in species portraying female social dominance over males or intense female–female competition, androgens might also play a role in mediating female health and fitness. We examined this hypothesis in the meerkat ( Suricata suricatta ), a cooperatively breeding, social carnivoran characterized by aggressively mediated female social dominance and extreme rank-related reproductive skew. Dominant females also have greater androgen concentrations and harbour greater parasite loads than their subordinate counterparts, but the relationship between concurrent androgen concentrations and parasite burdens is unknown. We found that a female's faecal androgen concentrations reliably predicted her concurrent state of endoparasitism irrespective of her social status: parasite species richness and infection by Spirurida nematodes, Oxynema suricattae , Pseudandrya suricattae and coccidia were greater with greater androgen concentrations. Based on gastrointestinal parasite burdens, females appear to experience the same trade-off in the costs and benefits of raised androgens as do the males of many species. This trade-off presumably represents a health cost of sexual selection operating in females.
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Chen, Yue, Jeffrey D. Zajac, and Helen E. MacLean. "Androgen regulation of satellite cell function." Journal of Endocrinology 186, no. 1 (July 2005): 21–31. http://dx.doi.org/10.1677/joe.1.05976.
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Androgen treatment can enhance the size and strength of muscle. However, the mechanisms of androgen action in skeletal muscle are poorly understood. This review discusses potential mechanisms by which androgens regulate satellite cell activation and function. Studies have demonstrated that androgen administration increases satellite cell numbers in animals and humans in a dose–dependent manner. Moreover, androgens increase androgen receptor levels in satellite cells. In vitro, the results are contradictory as to whether androgens regulate satellite cell proliferation or differentiation. IGF-I is one major target of androgen action in satellite cells. In addition, the possibility of non-genomic actions of androgens on satellite cells is discussed. In summary, this review focuses on exploring potential mechanisms through which androgens regulate satellite cells, by analyzing developments from research in this area.
10
Vanderschueren, Dirk, Liesbeth Vandenput, Steven Boonen, Marie K. Lindberg, Roger Bouillon, and Claes Ohlsson. "Androgens and Bone." Endocrine Reviews 25, no. 3 (June 1, 2004): 389–425. http://dx.doi.org/10.1210/er.2003-0003.
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Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs. Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERα. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERα pathways are involved in androgen action on radial bone growth. ERβ may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. Such androgen action on bone is mediated by the AR and ERα.
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Chen, Jiangang, MaryFran R. Sowers, Francisco M. Moran, Daniel S. McConnell, Nancy A. Gee, Gail A. Greendale, Cheryl Whitehead, Sidika E. Kasim-Karakas, and Bill L. Lasley. "Circulating Bioactive Androgens in Midlife Women." Journal of Clinical Endocrinology & Metabolism 91, no. 11 (November 1, 2006): 4387–94. http://dx.doi.org/10.1210/jc.2006-0284.
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Abstract Context: It is important to characterize the biological activity of circulating androgenic steroid hormones during the menopausal transition because these appear to impact the metabolic and cardiovascular health risk factors of women. Objective: The objective of the study was to develop and characterize a cell-based bioassay that measures the androgen receptor-mediated signal transduction in serum. Design: This was a clinically relevant experimental study nested in a sample population of a longitudinal cohort study. Setting: The study was conducted at a university laboratory. Methods: A receptor-mediated luciferase expression bioassay based on HEK 293 cells that were stably cotransfected with plasmids containing the human androgen receptor and luciferase gene was developed. In 49 samples from menstruating women aged 42–52 yr, total testosterone (T) and SHBG concentrations were measured by immunoassay; free T concentrations were calculated from the total T and SHBG concentrations. Results: Mean total T concentration of the sample was 1.15 nm (sd 0.46, range 0.57–3.86 nm). The mean bioactive androgen detected was 1.00 nm (sd 0.24, range 0.53–1.60 nm). Calculated free T (mean 0.0156 nm) was significantly lower than the levels of bioactive androgens measured by receptor-mediated bioassay. There was significant positive correlation between bioactive androgen levels and total T values in young women and polycystic ovarian disorder patients, whereas no correlation was found between the two values in middle-aged women. Conclusions: An androgen receptor-mediated bioassay can provide additional information in the evaluation of total bioactive androgens in midlife women. Our data suggest that levels of circulating SHBG may have a significant impact on the levels of total circulating bioavailable androgens.
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Wang, Po-Hsiang, Chang-Ping Yu, Tzong-Huei Lee, Ching-Wen Lin, Wael Ismail, Shiaw-Pyng Wey, An-Ti Kuo, and Yin-Ru Chiang. "Anoxic Androgen Degradation by the Denitrifying Bacterium Sterolibacterium denitrificans via the 2,3-seco Pathway." Applied and Environmental Microbiology 80, no. 11 (March 21, 2014): 3442–52. http://dx.doi.org/10.1128/aem.03880-13.
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ABSTRACTThe biodegradation of steroids is a crucial biochemical process mediated exclusively by bacteria. So far, information concerning the anoxic catabolic pathways of androgens is largely unknown, which has prevented many environmental investigations. In this work, we show thatSterolibacterium denitrificansDSMZ 13999 can anaerobically mineralize testosterone and some C19androgens. By using a13C-metabolomics approach and monitoring the sequential appearance of the intermediates, we demonstrated thatS. denitrificansuses the 2,3-secopathway to degrade testosterone under anoxic conditions. Furthermore, based on the identification of a C17intermediate, we propose that the A-ring cleavage may be followed by the removal of a C2side chain at C-5 of 17-hydroxy-1-oxo-2,3-seco-androstan-3-oic acid (the A-ring cleavage product) via retro-aldol reaction. The androgenic activities of the bacterial culture and the identified intermediates were assessed using thelacZ-based yeast androgen assay. The androgenic activity in the testosterone-grownS. denitrificansculture decreased significantly over time, indicating its ability to eliminate androgens. The A-ring cleavage intermediate (≤500 μM) did not exhibit androgenic activity, whereas the sterane-containing intermediates did. So far, only two androgen-degrading anaerobes (Sterolibacterium denitrificansDSMZ 13999 [a betaproteobacterium] andSteroidobacter denitrificansDSMZ 18526 [a gammaproteobacterium]) have been isolated and characterized, and both of them use the 2,3-secopathway to anaerobically degrade androgens. The key intermediate 2,3-seco-androstan-3-oic acid can be used as a signature intermediate for culture-independent environmental investigations of anaerobic degradation of C19androgens.
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Kolovou, Genovefa, Helen Bilianou, Apostolia Marvaki, and Dimitri P. Mikhailidis. "Aging Men and Lipids." American Journal of Men's Health 5, no. 2 (May 18, 2010): 152–65. http://dx.doi.org/10.1177/1557988310370360.
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Many theories aim at explaining the mechanisms of aging and death in humans. Decreased levels of androgens, growth hormone, and insulin-like growth factor accompany natural aging in men. Androgens influence the growth and maturation of men in various stages of their life. The action of androgens is performed by binding or not binding to androgen receptors. However, various actions of androgens were clarified after the discovery and genotyping of the androgen receptor. The influence of androgens on the lipid profile was reported by several researchers. This negative influence of androgens in men and the positive influence of estrogens in women are responsible for the higher impact of atherogenesis in men compared with women. In aging men, this negative influence of androgens on the lipid profile is more pronounced. This review considers the influence of age on lipid metabolism in men.
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Pernigoni, Nicolò, Elena Zagato, Arianna Calcinotto, Martina Troiani, Ricardo Pereira Mestre, Bianca Calì, Giuseppe Attanasio, et al. "Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis." Science 374, no. 6564 (October 8, 2021): 216–24. http://dx.doi.org/10.1126/science.abf8403.
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Microbes hijack prostate cancer therapy Androgens such as testosterone and dihydrotestosterone are essential for male reproduction and sexual function. Androgens can also influence the growth of prostate tumor cells, and androgen deprivation therapy (ADT) either by surgical means (castration) or pharmacological approaches (hormone suppression), is the cornerstone of current prostate cancer treatments. Pernigoni et al . found that when the body was deprived of androgens during ADT, the gut microbiome could produce androgens from androgen precursors (see the Perspective by McCulloch and Trinchieri). Gut commensal microbiota in ADT-treated patients or castrated mice produced androgens that were absorbed into the systemic circulation. These microbe-derived androgens appeared to favor the growth of prostate cancer and helped to facilitate development into a castration- or endocrine therapy–resistant state. —PNK
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O’Reilly, Michael W., Punith Kempegowda, Carl Jenkinson, Angela E. Taylor, Jonathan L. Quanson, Karl-Heinz Storbeck, and Wiebke Arlt. "11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 102, no. 3 (November 30, 2016): 840–48. http://dx.doi.org/10.1210/jc.2016-3285.
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Abstract Context: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS. Methods: One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four–hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded. Results: As expected, serum concentrations of the classic androgens testosterone (P < 0.001), androstenedione (P < 0.001), and dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P < 0.0001]. Obese (n = 51) and nonobese (n = 63) patients with PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance. Conclusions: We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.
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Zhang, Bin, Qiuqiong Cheng, Zhimin Ou, Jung Hoon Lee, Meishu Xu, Upasana Kochhar, Songrong Ren, Min Huang, Beth R. Pflug, and Wen Xie. "Pregnane X Receptor as a Therapeutic Target to Inhibit Androgen Activity." Endocrinology 151, no. 12 (October 20, 2010): 5721–29. http://dx.doi.org/10.1210/en.2010-0708.
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The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metabolism-based mechanism to reduce androgenic tone. PXR is a nuclear receptor previously known as a xenobiotic receptor regulating the expression of drug metabolizing enzymes and transporters. We showed that genetic (using a PXR transgene) or pharmacological (using a PXR agonist) activation of PXR lowered androgenic activity and inhibited androgen-dependent prostate regeneration in castrated male mice that received daily injections of testosterone propionate by inducing the expression of cytochrome P450 (CYP)3As and hydroxysteroid sulfotransferase (SULT)2A1, which are enzymes important for the metabolic deactivation of androgens. In human prostate cancer cells, treatment with the PXR agonist rifampicin (RIF) inhibited androgen-dependent proliferation of LAPC-4 cells but had little effect on the growth of the androgen-independent isogenic LA99 cells. Down-regulation of PXR or SULT2A1 in LAPC-4 cells by short hairpin RNA or small interfering RNA abolished the RIF effect, indicating that the inhibitory effect of RIF on androgens was PXR and SULT2A1 dependent. In summary, we have uncovered a novel function of PXR in androgen homeostasis. PXR may represent a novel therapeutic target to lower androgen activity and may aid in the treatment and prevention of hormone-dependent prostate cancer.
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Prizant, Hen, Norbert Gleicher, and Aritro Sen. "Androgen actions in the ovary: balance is key." Journal of Endocrinology 222, no. 3 (July 18, 2014): R141—R151. http://dx.doi.org/10.1530/joe-14-0296.
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For many decades, elevated androgens in women have been associated with poor reproductive health. However, recent studies have shown that androgens play a crucial role in women's fertility. The following review provides an overall perspective about how androgens and androgen receptor-mediated actions regulate normal follicular development, as well as discuss emerging concepts, latest perceptions, and controversies regarding androgen actions and signaling in the ovary.
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GELLER, JACK. "Overview of Enzyme Inhibitors and Anti‐Androgens in Prostatic Cancer." Journal of Andrology 12, no. 6 (November 12, 1991): 364–71. http://dx.doi.org/10.1002/j.1939-4640.1991.tb00274.x.
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AbstractSurgical castration and estrogen therapy for prostate cancer were developed in 1941, and have been shown to improve both quality of life and survival. Little change in the therapeutics of prostate cancer has occurred over the subsequent three decades. In the 1970s, the progestational anti‐androgens, ketoconazole and flutamide, were introduced as androgen‐blocking agents, and have been shown to block at least partially both adrenal and testicular androgens. Gonadotropin‐releasing hormone (GnRH) agonists were shown in the 1980s to produce medical castration without the cardiac and cerebrovascular risks of standard dose estrogen. In the 1980s, large‐scale, multicenter, double‐blind studies were done to compare the effect of combined androgen blockade, using multiple drugs, to single‐drug blockade of gonadal androgen with regard to time to progression and survival in stage D2 cancer. These studies were done to test theories regarding the role of adrenal androgens and their effects on androgen‐sensitive tumor clones in prostate cancer. The theory of clonal heterogeneity, particularly with regard to androgen sensitivity, has led to the continuation of three major controversies about the management of prostate cancer: Is combined blockade of testicular and adrenal androgens in stage D2 prostate cancer more effective than gonadal androgen blockade alone? What is the optimal secondary or tertiary therapy for relapsed prostate cancer? Is there any advantage for combined androgen blockade at the start of therapy in stage D2 prostate cancer as compared to sequential therapy with blockade of testicular androgens first, and then adrenal androgens at the time of relapse?
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Prescott, James L., and Donald J. Tindall. "Clathrin Gene Expression Is Androgen Regulated in the Prostate*." Endocrinology 139, no. 4 (April 1, 1998): 2111–19. http://dx.doi.org/10.1210/endo.139.4.5926.
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Abstract Androgens are required for the development and function of the prostate. In a normal human prostate, androgens control the synthesis of proteins such as prostate-specific antigen and human glandular kallikrein. The prostate secretes these proteins as well as a number of other compounds to form the prostatic fluid. Using differential display PCR to detect novel androgen-regulated genes, clathrin heavy chain expression was identified as potentially being up-regulated by androgens in the prostate cancer cell line LNCaP. We report here that the clathrin heavy chain and light chain genes are regulated by androgens. Clathrin heavy chain messenger RNA was up-regulated by androgens in a concentration- and time-specific manner in the LNCaP cell line. Translation of clathrin heavy chain messenger RNA was stimulated by androgens. Steady state levels of clathrin light chains a and b were up-regulated in the presence of androgen in LNCaP cells. Clathrin gene expression was examined in normal rat prostates, and similar results were found. Clathrin heavy chain protein levels in the rat prostate are also affected by the androgen status of the animal. We hypothesize that clathrin may be involved in the exocytosis of androgen-regulated secretory proteins such as prostate-specific antigen and human glandular kallikrein.
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Rozhivanov, Roman V., Elena N. Andreeva, Galina A. Melnichenko, and Natalya G. Mokrysheva. "Androgens and Antiandrogens influence on COVID-19 disease in men." Problems of Endocrinology 66, no. 4 (December 7, 2020): 77–81. http://dx.doi.org/10.14341/probl12500.
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The WHO has declared a SARS-CoV-2 pandemic. During a pandemic, the researches aimed at finding the new treatments for SARS-CoV-2 become relevant. The review focuses on studies of androgens and antiandrogens in this disease. Since the beginning of the COVID-19 epidemic, it has been noted that men have more severe forms of infection and higher mortality. The main cause of both the severity of the disease and the high mortality of men from COVID-19 are associated with androgens. It was found that patients receiving androgen deprivation are less likely to become infected and easily tolerate COVID-19. The researchers explain the effect of the therapy by the effect on the TMPRSS2 protein. It was found that both TMPRSS2 expression and a more severe course of coronavirus infection are observed in men with hyperandrogenism – androgenic alopecia, acne, excessive facial hair growth and increased skin oiliness. In this regard, some researchers suggest to use androgen deprivation for men at high risk of developing COVID-19. Steroid and non-steroidal antiandrogens are used for androgen deprivation. At the same time, obtaned scientific data on the relationship of severe forms and mortality of COVID-19 with low testosterone levels leads to a hypothesis about the possibility of a positive effect not of androgen devrivation therapy but of androgen replacement therapy in case of hypogonadism have diagnosed. These studies have not been completed recently, and data on the effectiveness and safety of antiandrogens and androgens in the treatment of a new coronavirus infection require clarification.
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Zhou, Ye, Maya Otto-Duessel, Miaoling He, Susan Markel, Tim Synold, and Jeremy O. Jones. "Low systemic testosterone levels induce androgen maintenance in benign rat prostate tissue." Journal of Molecular Endocrinology 51, no. 1 (May 24, 2013): 143–53. http://dx.doi.org/10.1530/jme-13-0060.
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Prostate cancer (PC) is both an age- and an androgen-dependent disease. Paradoxically, systemic levels of androgens decline with age as the risk of PC rises. While there is no correlation between systemic androgen levels and the risk of PC, systemic androgen levels do not reflect the levels of androgens in prostate tissue. In metastatic PC, changes in the androgen biosynthesis pathway during hormone therapy result in increased levels of androgens in cancer tissue and contribute to continued androgen receptor (AR) signaling. It is possible that similar changes occur in normal prostate tissue as androgen levels decline with age and that this contributes to tumorigenesis. In the present study, we sought to determine whether the rat prostate is able to maintain functional levels of androgens despite low serum testosterone levels. Rats were castrated and implanted with capsules to achieve castrate, normal, sub-physiological, and supra-physiological levels of testosterone. After 6 weeks of treatment, LC–MS/MS was used to quantify the levels of testosterone and dihydrotestosterone (DHT) in the serum and prostate tissue. Quantitative RT-PCR was used to quantify the expression of genes involved in the androgen/AR signaling axis. Despite significantly different levels of testosterone and DHT being present in the serum, testosterone and DHT concentrations in prostate tissue from different testosterone-treatment groups were very similar. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all the testosterone-treatment groups, demonstrating that the rat prostate can maintain a functional level of androgens despite low serum testosterone levels. Low-testosterone treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining functional androgen levels.
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Gibson, Douglas A., Ioannis Simitsidellis, Frances Collins, and Philippa T. K. Saunders. "Evidence of androgen action in endometrial and ovarian cancers." Endocrine-Related Cancer 21, no. 4 (February 28, 2014): T203—T218. http://dx.doi.org/10.1530/erc-13-0551.
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Endometrial cancer (EC) and ovarian cancer are common gynaecological malignancies. The impact of androgen action in these cancers is poorly understood; however, there is emerging evidence to suggest that targeting androgen signalling may be of therapeutic benefit. Epidemiological evidence suggests that there is an increased risk of EC associated with exposure to elevated levels of androgens, and genetic variants in genes related to both androgen biosynthesis and action are associated with an increased risk of both EC and ovarian cancer. Androgen receptors (ARs) may be a potential therapeutic target in EC due to reported anti-proliferative activities of androgens. By contrast, androgens may promote growth of some ovarian cancers and anti-androgen therapy has been proposed. Introduction of new therapies targeting ARs expressed in EC or ovarian cancer will require a much greater understanding of the impacts of cell context-specific AR-dependent signalling and how ARs can crosstalk with other steroid receptors during progression of disease. This review considers the evidence that androgens may be important in the aetiology of EC and ovarian cancer with discussion of evidence for androgen action in normal and malignant endometrial and ovarian tissue.
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Savantri, Duragappa, and Madhava Diggavi. "A REVIEW ON CLINICAL APPLICATION OF SUKRAKSHAYA AND KSHEENASUKRA LAKSHANAS WITH RESPECT TO ANDROGEN DEFICIENCY." International Journal of Research in Ayurveda and Pharmacy 12, no. 1 (March 2, 2021): 146–49. http://dx.doi.org/10.7897/2277-4343.120133.
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Sukra is the essence of all Dhatus and responsible for the both Prakruta and Vikruta function on the Body in Physiological and Pathological conditions respectively. Androgens are the male gonadal hormones and maintain the male reproductive functions. Acharya Sushruta clears that Sukradhara kala is present in all living organisms and all over the body as like Circulating Androgens in the blood. The dysfunction of Sukra Dhatu will affect all over the body by means of Many Causative factors (Nidanas) or Secondary affection as a result of many systemic disorders. In Bruhatrayi and Laghutrayee explained Ksheena sukra lakshana and Sukrakshaya lakshana to understand Sukra dushti. Here sukra denotes Semen plus androgen. Hyper and hypo androgenic action cause many diseases and itself will get affect by the influence of many systemic disorders so one should meticulously to be evaluated in most of the diseases even other than infertility cases for Sukrakshaya and androgen deficiency.
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Ciaccio, Marta, Marco Rivarola, and Alicia Belgorosky. "Decrease of serum sex hormone-binding globulin as a marker of androgen sensitivity. Correlation with clinical response." Acta Endocrinologica 120, no. 4 (April 1989): 540–44. http://dx.doi.org/10.1530/acta.0.1200540.
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Abstract. An evaluation of the usefulness of determining the decrease in serum sex hormone-binding globulin after exogenous testosterone was studied in 55 prepubertal patients with ambiguous external genitalia or micropenis. The biochemical response (androgen sensitivity test) was compared with the clinical response as judged by signs of androgen stimulation of external genitalia. Patients were divided in two groups according to age. Group I, 11 patients younger than 3 months and Group II, 44 patients older than 3 months. Only in 54% of Group I was there a correlation between the androgen sensitivity test and the clinical response to androgens in either a positive (4 patients) or negative sense (2 patients). On the other hand, the androgen sensitivity test and the clinical response to androgens correlated in 91% of the patients of Group II in either a positive (35 patients) or negative sense (5 patients). Two of the 4 patients with lacking correlation had a negative androgen sensitivity test and micropenis secondary to pituitary deficiency. It is concluded that in prepubertal patients older than 3 months with abnormalities of sex differentiation, the androgen sensitivity test and the clinical response to androgens are useful for evaluating androgen sensitivity. The clinical response to androgens is useful in early life when a positive response is found.
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Peng, Lihong, Peter J. Malloy, Jining Wang, and David Feldman. "Growth Inhibitory Concentrations of Androgens Up-Regulate Insulin-Like Growth Factor Binding Protein-3 Expression via an Androgen Response Element in LNCaP Human Prostate Cancer Cells." Endocrinology 147, no. 10 (October 1, 2006): 4599–607. http://dx.doi.org/10.1210/en.2006-0560.
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IGF binding protein-3 (IGFBP-3), the most abundant circulating IGF binding protein, inhibits cell growth and induces apoptosis by both IGF-I-dependent and -independent pathways. The ability of IGFBP-3 to inhibit tumor growth has been demonstrated in many cancers including prostate cancer (PCa). High concentrations of androgens, which inhibit the growth of the LNCaP human PCa cell line, have been shown to have both positive and negative effects on IGFBP-3 expression by different laboratories. To further explore the relationship between IGFBP-3 and androgens, we examined IGFBP-3 expression in LNCaP cells. We demonstrate that IGFBP-3 expression can be induced by 10 nm of the synthetic androgen R1881 or dihydrotestosterone. Transactivation assays show that the 6-kb IGFBP-3 promoter sequence directly responds to androgen treatment. In silico analysis identified a putative androgen response element (ARE) at −2879/−2865 in the IGFBP-3 promoter. A single point mutation in this ARE disrupted transactivation by R1881. Combining the data obtained from EMSA, chromatin immunoprecipitation and mutational analysis, we conclude that a novel functional ARE is present in the IGFBP-3 promoter that directly mediates androgen induction of IGFBP-3 expression. Furthermore, we found that the combination of androgens and calcitriol significantly potentiated the IGFBP-3 promoter activity, suggesting that enhanced induction of the expression of the endogenous IGFBP-3 gene may contribute to the greater inhibition of LNCaP cell growth by combined calcitriol and androgens. Because androgens are well known to stimulate PCa growth and androgen deprivation therapy causes PCa to regress, the stimulation by androgens of this antiproliferative and proapoptotic protein is paradoxical and raises interesting questions about the role of androgen-stimulated IGFBP-3 in PCa.
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Gilliver, Stephen, Fred Wu, and Gillian Ashcroft. "Regulatory roles of androgens in cutaneous wound healing." Thrombosis and Haemostasis 90, no. 12 (2003): 978–85. http://dx.doi.org/10.1160/th03-05-0302.
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SummaryAlthough the effects of androgens on wound healing are poorly characterised, the androgen receptor is expressed by inflammatory cells, keratinocytes and fibroblasts during wound healing, suggesting that androgens may regulate inflammatory and/or repair processes. In fact, it appears that endogenous testosterone inhibits wound healing and promotes inflammation since castration of male mice or systemic treatment with the androgen receptor antagonist flutamide accelerates cutaneous wound healing and reduces the inflammatory response. The aim of this review is to summarise our current knowledge about the regulation of tissue repair processes by androgens.
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Page, Stephanie T., Daniel W. Lin, Elahe A. Mostaghel, David L. Hess, Lawrence D. True, John K. Amory, Peter S. Nelson, Alvin M. Matsumoto, and William J. Bremner. "Persistent Intraprostatic Androgen Concentrations after Medical Castration in Healthy Men." Journal of Clinical Endocrinology & Metabolism 91, no. 10 (October 1, 2006): 3850–56. http://dx.doi.org/10.1210/jc.2006-0968.
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Abstract Context: The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences. Objective: The objective of the study was to determine the effect of serum androgen manipulation on intraprostatic androgens in normal men. Design: Thirteen male volunteers ages 35–55 yr (prostate-specific antigen < 2.0 ng/ml; normal transrectal ultrasound) were randomly assigned to: 1) a long-acting GnRH-antagonist, acyline, every 2 wk; 2) acyline plus testosterone (T) gel (10 mg/d); or 3) placebo for 28 d. Serum hormones were assessed weekly. Prostate biopsies were obtained on d 28. Extracted androgens were measured by RIA, and immunohistochemistry for androgen-regulated proteins was performed. Results: The mean decrease in serum T was 94%, whereas prostatic T and dihydrotestosterone levels were 70 and 80% lower, respectively, in subjects receiving acyline alone compared with controls (P < 0.05). Despite this decrease in prostate androgens, there were no detectable differences in prostate epithelial proliferation, apoptosis, prostate-specific antigen, and androgen receptor expression. Conclusion: In this small study of healthy subjects, despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20–30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected. Our data highlight the importance of assessing tissue hormone levels. The source of persistent prostate androgens associated with medical castration and their potential role in supporting prostate metabolism deserves further study.
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Monks, Douglas A., Will Kopachik, S. Marc Breedlove, and Cynthia L. Jordan. "Anabolic responsiveness of skeletal muscles correlates with androgen receptor protein but not mRNA." Canadian Journal of Physiology and Pharmacology 84, no. 2 (February 2006): 273–77. http://dx.doi.org/10.1139/y05-157.
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Anabolic effects of androgens on skeletal muscle are well documented, but the physiological and biochemical bases of these effects are poorly understood. Skeletal muscles that differ in their androgen responsiveness can be used to examine these mechanisms. We compared androgen receptor mRNA and protein levels of the rat levator ani, a perineal skeletal muscle that depends on androgens for its normal maintenance and function with that of the rat extensor digitorum longus, a limb muscle that does not require androgens. Western immunoblotting indicated that androgen receptor protein is significantly elevated in the levator ani relative to the extensor digitorum longus. Surprisingly, steady state androgen receptor mRNA levels were equivalent in these muscles, as determined by Northern blot analysis and quantitative RT-PCR. These results suggest that androgen responsiveness of skeletal muscles is determined by the level of androgen receptor protein in a particular muscle and that androgen receptor protein content is regulated by translational or post-translational mechanisms.
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Browne, P., N. J. Place, J. D. Vidal, I. T. Moore, G. R. Cunha, S. E. Glickman, and A. J. Conley. "Endocrine differentiation of fetal ovaries and testes of the spotted hyena (Crocuta crocuta): timing of androgen-independent versus androgen-driven genital development." Reproduction 132, no. 4 (October 2006): 649–59. http://dx.doi.org/10.1530/rep.1.01120.
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Female spotted hyenas (Crocuta crocuta) have an erectile peniform clitoris and a pseudoscrotum but no external vagina, all established by day 35 of a 110-day gestation. Recent studies indicate that these events are androgen-independent, although androgen secretion by fetal ovaries and testis was hypothesized previously to induce phallic development in both sexes. We present the first data relating to the capacity of the ovaries and testes of the spotted hyena to synthesize androgens at different stages of fetal life. Specifically, spotted hyena fetal gonads were examined by immunohistochemistry at GD 30, 45, 48, 65, and 95 for androgen-synthesizing enzymes, as related to the morphological development. Enzymes included 17α-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5, 3β-hydroxysteroid dehydrogenase (3βHSD), and cholesterol side-chain cleavage cytochrome P450 (P450scc). Anti-Müllerian-hormone (AMH) expression was also examined. AMH was strongly expressed in fetal Sertoli cells from GD 30 and after. P450c17 expression was detected in Leydig cells of developing testes and surprisingly in Müllerian duct epithelium. Fetal ovaries began to organize and differentiate by GD 45, and medullary cells expressed P450c17, cytochrome b5, 3βHSD, and P450scc. The findings support the hypothesis that external genital morphology is probably androgen-independent initially, but that fetal testicular androgens modify the secondary, male-specific phallic form and accessory organs. Fetal ovaries appear to develop substantial androgen-synthesizing capacity but not until phallic differentiation is complete, i.e. after GD 45 based on circulating androstenedione concentrations. During late gestation, fetal ovaries and testes synthesize androgens, possibly organizing the neural substrates of aggressive behaviors observed at birth in spotted hyenas. These data provide an endocrine rationale for sexual dimorphisms in phallic structure and reveal a potential source of androgenic support for neonatal aggression in female and male C. crocuta.
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Davies, Susan R. "Androgens and the Menopause." British Menopause Society Journal 4, no. 3 (September 1998): 87–94. http://dx.doi.org/10.1177/136218079800400305.
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The menopause results in acute reductions in circulating levels of oestradiol, and hence standard hormone replacement therapy is oestrogen based. There is now increasing interest in the physiological sequelae to the declining levels of circulating androgens which occur in women with increasing age. Women who have undergone a surgical menopause may experience a variety of physical symptoms secondary to their reduced androgen levels and can be offered testosterone replacement. Women who undergo natural menopause may also have symptoms secondary to androgen depletion and similarly may benefit by the use of testosterone. This review addresses the changes in androgens in women with age and the rationale for physiological androgen replacement as part of a hormone replacement therapy regimen in postmenopausal women.
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Koryakin, M. V., A. S. Akopyan, and V. I. Vasiliev. "On the correlation of androgens of the testes and adrenal glands with hypogonadism." Problems of Endocrinology 44, no. 1 (February 1, 1998): 27–30. http://dx.doi.org/10.14341/probl199844127-30.
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Examinations of 14 healthy males, including measurements of the main adrenal and testicular androgens and their precursors, estradiol, and pituitary gonadotropic hormones in the peripheral blood, revealed that the levels of the main adrenal and testicular androgens do not correlate. Assessment of the hormonal status of 24 patients with hypogonadism showed that a deficit in the production of testicular androgens is not compensated for by hyperproduction of adrenal androgens. Testosterone production in patients with acquired anorchism, who were never administered substitute androgen therapy, is about 1/12 of this hormone’s production in health. Hence, the secretion of testicular and adrenal androgens is regulated by different mechanisms.
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Walters, K. A., V. Rodriguez Paris, A. Aflatounian, and D. J. Handelsman. "Androgens and ovarian function: translation from basic discovery research to clinical impact." Journal of Endocrinology 242, no. 2 (August 2019): R23—R50. http://dx.doi.org/10.1530/joe-19-0096.
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In the last decade, it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar-knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.
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Randall, V. A., M. J. Thornton, and A. G. Messenger. "Cultured dermal papilla cells from androgen-dependent human hair follicles (e.g. beard) contain more androgen receptors than those from non-balding areas of scalp." Journal of Endocrinology 133, no. 1 (April 1992): 141–47. http://dx.doi.org/10.1677/joe.0.1330141.
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ABSTRACT Androgens stimulate hair growth in many areas, e.g. the beard; they also induce regression and balding on the scalp with increasing age in genetically disposed individuals. The cause(s) of this biological conundrum is unknown but age-related; androgen-potentiated changes also occur in the prostate. The mesenchymederived dermal papilla situated at the base of the hair follicle is thought to play an important role in regulating the growth and development of the follicular epithelium. Since androgens probably act on the hair follicle via the dermal papilla, cultures of dermal papilla cells from human hair follicles with differing responses to androgens in vivo have been established and their ability to bind androgens assessed. Receptor binding was assayed by saturation analysis (0·05–10 nmol/l) using the synthetic non-metabolizable androgen, [3H]mibolerone. Shionogi 115 cells were also assayed as a positive control. Specific high-affinity low-capacity androgen receptors were identified in 12 dermal papilla primary cell lines with similar characteristics to established androgen receptors. Cells from androgen-sensitive follicles (beard, scrotum and pubis) contained higher levels of androgen receptors than those derived from relatively androgeninsensitive non-balding scalp follicles whether the receptor content was calculated in relation to cell number, protein or DNA content of the cells. These results support the hypothesis that androgens act on hair follicles via the dermal papilla in vivo and demonstrate that dermal papilla cells exhibit an altered phenotype in culture which depends on the body site from which they were derived. Cultured human dermal papilla cells should prove a useful model system for studies of the mechanism of androgen action, and further investigations may elucidate the paradox of why bald men can grow beards. Journal of Endocrinology (1992) 133, 141–147
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Baratta, M., S. Grolli, A. Poletti, R. Ramoni, M. Motta, and C. Tamanini. "Role of androgens in proliferation and differentiation of mouse mammary epithelial cell line HC11." Journal of Endocrinology 167, no. 1 (October 1, 2000): 53–60. http://dx.doi.org/10.1677/joe.0.1670053.
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Androgens have been found in mammary epithelium and in milk throughout the cycle of the mammary gland in vivo. The aim of this study was to investigate the possible role of these substances in mammary epithelial growth and differentiation in the mouse HC11 cell line. Cells were stimulated with testosterone, dihydrotestosterone, androstenedione and 5alpha-androstane-3alpha,17beta-diol at concentrations ranging between 0.3 nM and 30 nM. Cyproterone acetate or flutamide, androgen receptor antagonists, (3 microM) were used to block specific androgen effects. Proliferative effects were measured by an MTT (tetrazolium blue) conversion test and [(3)H]thymidine uptake. HC11 cells were transfected with pbetacCAT, a chimeric rat beta-casein gene promoter-chloramphenicol acetyl transferase (CAT) gene construct and CAT ELISA was used to determine gene expression. RT-PCR was performed to detect androgen receptor expression. After 24, 48 and 72 h androgens significantly (P<0.05) increased proliferation. Androgen antagonists significantly (P<0.05) reduced the proliferative effects. Furthermore androgens potentiated the lactogenic effect of prolactin, insulin and dexamethasone (P<0.05). Finally, the androgen receptor gene was expressed in both proliferating and differentiated HC11 cells. These observations lead us to hypothesize an activity of this class of steroids in mammary physiology. In particular, androgens stimulate cell proliferation and beta-casein gene expression; this influence appears to be mediated by androgen receptors.
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Sharifi, Nima. "Minireview: Androgen Metabolism in Castration-Resistant Prostate Cancer." Molecular Endocrinology 27, no. 5 (May 1, 2013): 708–14. http://dx.doi.org/10.1210/me.2013-1007.
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Abstract The decades-old terminology of androgen independence has been replaced in recent years with castration-resistant prostate cancer. Biological and clinical evidence have together conspired to support the use of this revised terminology by demonstrating that in the vast majority of cases tumors are neither truly depleted of androgens, nor are they free of the requirement for androgens to sustain growth and progression. Abiraterone acetate, an androgen synthesis inhibitor, and enzalutamide, a potent androgen receptor antagonist, both exploit the continued requirement for androgens. A central question, given the therapeutic gains enabled by further suppression of the androgen axis with these newer agents, is whether there may be additional clinical benefit gained by moving the goal posts of androgen suppression even further. The answer lies in part with the mechanisms utilized by tumors that enable resistance to these therapies. The aims of this review were to give a broad outline of steroidogenesis in prostate cancer and to highlight recent developments in understanding resistance to hormonal therapies.
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Azamkulova, N. O., and Sevara Irgasheva. "CLINICAL COURSE OF PERIMENOPAUSAL PERIOD IN WOMEN WITH HYPERANDROGENISM SYNDROME." UZBEK MEDICAL JOURNAL 2, no. 5 (May 30, 2021): 25–29. http://dx.doi.org/10.26739/2181-0664-2021-5-5.
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Hyperandrogenism is a disorder of endocrine status caused by excess production of androgens. The syndrome is a consequence of increased androgen production both in the ovaries and adrenal glands. However, such a division is very arbitrary, as increased production of androgens in the adrenal glands may increase production in the ovaries and vice versa. Androgens in women are synthesized by ovaries, adrenal glands and peripheral tissues, which also participate in metabolism.The set of androgens in both womenand men includes dehydroepiandrosterone-sulfate, dehydroepiandrosterone, androstenedione, testosterone and 5-alpha-dihydrotestosterone (5-alpha-DHT). Still, unlike men, women have a higher concentration of the first three hormones than the lasttwo. Androgen synthesis in the adrenal glands in women is regulated by adrenocorticotropic and in the ovaries by luteinizing hormone (LH) and some other intraglandular autoparacrine mechanisms. According to recent studies, in addition to the basic biological, previously commonly known effects of androgens, their new mechanisms of influence on the female body have been discovered. Keywords: hyperandrogenism, hormones, ovaries, adrenal glands, reproductive disorders
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Champlin, RE, WG Ho, SA Feig, DJ Winston, C. Lenarsky, and RP Gale. "Do androgens enhance the response to antithymocyte globulin in patients with aplastic anemia? A prospective randomized trial." Blood 66, no. 1 (July 1, 1985): 184–88. http://dx.doi.org/10.1182/blood.v66.1.184.184.
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Abstract We analyzed the effect of antithymocyte globulin (ATG) with or without androgens in 121 patients with aplastic anemia. Fifty-three patients with moderate to severe aplastic anemia were prospectively randomized to receive ATG with or without oral androgens. Eleven of 26 patients (42%) receiving ATG plus androgen responded, including three complete and eight partial responses. Twelve of 27 patients (44%) receiving ATG plus placebo responded, including five complete and seven partial responses. The difference in response rates was not significant (P greater than .9). Survival was also comparable in the two groups; for patients with severe aplastic anemia, actuarial survival at two years was 55% +/- 24% (95% confidence interval) in patients receiving ATG plus androgen compared with 50% +/- 24% in the ATG plus placebo group (P = .65). Furthermore, results in both groups were indistinguishable from those obtained in 68 historical controls receiving ATG without androgens. These data indicate that androgens are not required in order to respond to antithymocyte globulin and the addition of androgens, as used in this trial, did not significantly improve response rates to ATG treatment.
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Champlin, RE, WG Ho, SA Feig, DJ Winston, C. Lenarsky, and RP Gale. "Do androgens enhance the response to antithymocyte globulin in patients with aplastic anemia? A prospective randomized trial." Blood 66, no. 1 (July 1, 1985): 184–88. http://dx.doi.org/10.1182/blood.v66.1.184.bloodjournal661184.
Full textAbstract:
We analyzed the effect of antithymocyte globulin (ATG) with or without androgens in 121 patients with aplastic anemia. Fifty-three patients with moderate to severe aplastic anemia were prospectively randomized to receive ATG with or without oral androgens. Eleven of 26 patients (42%) receiving ATG plus androgen responded, including three complete and eight partial responses. Twelve of 27 patients (44%) receiving ATG plus placebo responded, including five complete and seven partial responses. The difference in response rates was not significant (P greater than .9). Survival was also comparable in the two groups; for patients with severe aplastic anemia, actuarial survival at two years was 55% +/- 24% (95% confidence interval) in patients receiving ATG plus androgen compared with 50% +/- 24% in the ATG plus placebo group (P = .65). Furthermore, results in both groups were indistinguishable from those obtained in 68 historical controls receiving ATG without androgens. These data indicate that androgens are not required in order to respond to antithymocyte globulin and the addition of androgens, as used in this trial, did not significantly improve response rates to ATG treatment.
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Roşca, Adrian Eugen, Ana-Maria Vlădăreanu, Alina Mititelu, Bogdan Ovidiu Popescu, Corin Badiu, Constantin Căruntu, Suzana Elena Voiculescu, et al. "Effects of Exogenous Androgens on Platelet Activity and Their Thrombogenic Potential in Supraphysiological Administration: A Literature Review." Journal of Clinical Medicine 10, no. 1 (January 4, 2021): 147. http://dx.doi.org/10.3390/jcm10010147.
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Anabolic androgenic steroids (AAS), simply called “androgens”, represent the most widespread drugs used to enhance performance and appearance in a sporting environment. High-dosage and/or long-term AAS administration has been associated frequently with significant alterations in the cardiovascular system, some of these with severe endpoints. The induction of a prothrombotic state is probably the most life-threatening consequence, suggested by numerous case reports in AAS-abusing athletes, and by a considerable number of human and animal studies assessing the influence of exogenous androgens on hemostasis. Despite over fifty years of research, data regarding the thrombogenic potential of exogenous androgens are still scarce. The main reason is the limited possibility of conducting human prospective studies. However, human observational studies conducted in athletes or patients, in vitro human studies, and animal experiments have pointed out that androgens in supraphysiological doses induce enhanced platelet activity and thrombopoiesis, leading to increased platelet aggregation. If this tendency overlaps previously existing coagulation and/or fibrinolysis dysfunctions, it may lead to a thrombotic diathesis, which could explain the multitude of thromboembolic events reported in the AAS-abusing population. The influence of androgen excess on the platelet activity and fluid–coagulant balance remains a subject of debate, urging for supplementary studies in order to clarify the effects on hemostasis, and to provide new compelling evidence for their claimed thrombogenic potential.
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de Waal, P. P., D. S. Wang, W. A. Nijenhuis, R. W. Schulz, and J. Bogerd. "Functional characterization and expression analysis of the androgen receptor in zebrafish (Danio rerio) testis." REPRODUCTION 136, no. 2 (August 2008): 225–34. http://dx.doi.org/10.1530/rep-08-0055.
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The biological activity of androgens, important for male sexual differentiation and development, is mediated by the androgen receptor (AR) that binds to specific DNA recognition sites regulating the transcription of androgen target genes. We investigated androgen production by adult zebrafish testis tissue, and identified 11β-hydroxyandrostenedione, 11-ketoandrostenedione (OA), and 11-ketotestosterone (11-KT) as main products, and hence potential ligands, for the zebrafish Ar. These androgens were then included in the pharmacological characterization of the zebrafish Ar. The zebrafish Ar responded well in terms of binding and transactivation to synthetic androgens as well as to testosterone and 11-KT, and reasonably well to OA and androstenedione. In situ hybridization analysis of zebrafish testis revealed that ar mRNA expression was detected in the subpopulation of Sertoli cells contacting early spermatogonia.
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Labrie, F., V. Luu-The, A. Bélanger, S.-X. Lin, J. Simard, G. Pelletier, and C. Labrie. "Is dehydroepiandrosterone a hormone?" Journal of Endocrinology 187, no. 2 (November 2005): 169–96. http://dx.doi.org/10.1677/joe.1.06264.
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Dehydroepiandrosterone (DHEA) is not a hormone but it is a very important prohormone secreted in large amounts by the adrenals in humans and other primates, but not in lower species. It is secreted in larger quantities than cortisol and is present in the blood at concentrations only second to cholesterol. All the enzymes required to transform DHEA into androgens and/or estrogens are expressed in a cell-specific manner in a large series of peripheral target tissues, thus permitting all androgen-sensitive and estrogen-sensitive tissues to make locally and control the intracellular levels of sex steroids according to local needs. This new field of endocrinology has been called intracrinology. In women, after menopause, all estrogens and almost all androgens are made locally in peripheral tissues from DHEA which indirectly exerts effects, among others, on bone formation, adiposity, muscle, insulin and glucose metabolism, skin, libido and well-being. In men, where the secretion of androgens by the testicles continues for life, the contribution of DHEA to androgens has been best evaluated in the prostate where about 50% of androgens are made locally from DHEA. Such knowledge has led to the development of combined androgen blockade (CAB), a treatment which adds a pure anti-androgen to medical (GnRH agonist) or surgical castration in order to block the access of the androgens made locally to the androgen receptor. In fact, CAB has been the first treatment demonstrated to prolong life in advanced prostate cancer while recent data indicate that it can permit long-term control and probably cure in at least 90% of cases of localized prostate cancer. The new field of intracrinology or local formation of sex steroids from DHEA in target tissues has permitted major advances in the treatment of the two most frequent cancers, namely breast and prostate cancer, while its potential use as a physiological HRT could well provide a physiological balance of androgens and estrogens, thus offering exciting possibilities for women’s health at menopause.
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Schiffer, Lina, Alicia Bossey, Punith Kempegowda, Angela E. Taylor, Ildem Akerman, Dagmar Scheel-Toellner, Karl-Heinz Storbeck, and Wiebke Arlt. "Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens." European Journal of Endocrinology 184, no. 3 (March 2021): 357–67. http://dx.doi.org/10.1530/eje-20-1077.
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Objective Androgens are important modulators of immune cell function. The local generation of active androgens from circulating precursors is an important mediator of androgen action in peripheral target cells or tissues. We aimed to characterize the activation of classic and 11-oxygenated androgens in human peripheral blood mononuclear cells (PBMCs). Methods PBMCs were isolated from healthy male donors and incubated ex vivo with precursors and active androgens of the classic and 11-oxygenated androgen pathways. Steroids were quantified by liquid chromatography-tandem mass spectrometry. The expression of genes encoding steroid-metabolizing enzymes was assessed by quantitative PCR. Results PBMCs generated eight-fold higher amounts of the active 11-oxygenated androgen 11-ketotestosterone than the classic androgen testosterone from their respective precursors. We identified the enzyme AKR1C3 as the major reductive 17β-hydroxysteroid dehydrogenase in PBMCs responsible for both conversions and found that within the PBMC compartment natural killer cells are the major site of AKRC13 expression and activity. Steroid 5α-reductase type 1 catalyzed the 5α-reduction of classic but not 11-oxygenated androgens in PBMCs. Lag time prior to the separation of cellular components from whole blood increased serum 11-ketotestosterone concentrations in a time-dependent fashion, with significant increases detected from two hours after blood collection. Conclusions 11-Oxygenated androgens are the preferred substrates for androgen activation by AKR1C3 in PBMCs, primarily conveyed by natural killer cell AKR1C3 activity, yielding 11-ketotestosterone the major active androgen in PBMCs. Androgen metabolism by PBMCs can affect the results of serum 11-ketotestosterone measurements, if samples are not separated in a timely fashion. Significance statement We show that human peripheral blood mononuclear cells (PBMCs) preferentially activate 11-ketotestosterone rather than testosterone when incubated with precursors of both the classic and the adrenal-derived 11-oxygenated androgen biosynthesis pathways. We demonstrate that this activity is catalyzed by the enzyme AKR1C3, which we found to primarily reside in natural killer cells, major contributors to the anti-viral immune defense. This potentially links intracrine 11-oxygenated androgen generation to the previously observed decreased NK cell cytotoxicity and increased infection risk in primary adrenal insufficiency. In addition, we show that PBMCs continue to generate 11-ketotestosterone if the cellular component of whole blood samples is not removed in a timely fashion, which could affect measurements of this active androgen in routine clinical biochemistry.
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Hickson, R. C., T. T. Kurowski, T. M. Galassi, D. G. Daniels, and R. J. Chatterton Jr. "Androgen cytosol binding during compensatory overload-induced skeletal muscle hypertrophy." Canadian Journal of Biochemistry and Cell Biology 63, no. 5 (May 1, 1985): 348–54. http://dx.doi.org/10.1139/o85-051.
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This study was undertaken to evaluate whether the increased androgen cytosol binding is an early or later event in the sequence of skeletal muscle hypertrophy induced by surgical overload. Following removal of the synergistic gastrocnemius and soleus muscles, plantaris muscle weights of overloaded hypophysectomized male rats were heavier than those in the controls by 29% at 2 days, 41% at 7 days, 38% at 14 days, and 47% at 35 days. Androgen cytosol receptor binding capacities (femtomoles per milligram protein), determined using a synthetic androgen, [3H]methyltrienolone (R1881), were higher than observed in muscles of controls at all points of muscle enlargement. At high concentrations of labeled ligand, Scatchard analyses became nonlinear and were resolved using a two-component binding model. Receptor capacity of the higher affinity "androgenic component" for methyltrienolone binding in plantaris muscles was lower at 2 days but 60–80% higher at 7, 14, and 35 days in the hypertrophied group than in the control group. The lower affinity "glucocorticoid component" was higher in the overloaded group at all points following surgery. Several glucocorticoids and estradiol-17β competed equally with androgens for methyltrienolone binding. However, when cytosol s were incubated with triamcinolone acetonide to block methyltrienolone binding to glucocorticoid receptors, the androgenic component was highly specific for androgens. These results show that total [3H]methyltrienolone cytosol concentrations increased in parallel with the muscle hypertrophy, yet the individual components of methyltrienolone binding attained greater concentrations in overloaded muscles by an apparently different sequence of events.
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Hibberts, NA, AE Howell, and VA Randall. "Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp." Journal of Endocrinology 156, no. 1 (January 1, 1998): 59–65. http://dx.doi.org/10.1677/joe.0.1560059.
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Androgens can gradually transform large scalp hair follicles to smaller vellus ones, causing balding. The mechanisms involved are unclear, although androgens are believed to act on the epithelial hair follicle via the mesenchyme-derived dermal papilla. This study investigates whether the levels and type of androgen receptors in primary lines of cultured dermal papilla cells derived from balding scalp hair follicles differ from those of follicles from non-balding scalp. Androgen receptor content was measured by saturation analysis using the non-metabolisable androgen, [3H]mibolerone (0.05-10 nM) in a 9-10 point assay. Pubic dermal fibroblasts and Shionogi cells were examined as positive controls. Repetitive assays of Shionogi cells showed good precision in the levels of androgen receptor content (coefficient of variation = 3.7%). Specific, high affinity, low capacity androgen receptors were detected in dermal papilla cells from both balding and non-balding follicles. Balding cells contained significantly (P < 0.01) greater levels of androgen receptors (Bmax = 0.06 +/- 0.01 fmol/10(4) cells (mean +/- S.E.M.)) than those from non-balding scalp (0.04 +/- 0.001). Competition studies with a range of steroids showed no differences in receptor binding specificity in the two cell types. The higher levels of androgen receptors in cells from balding scalp hair follicles with similar properties to those from non-balding scalp concur with the expectations from their in vivo responses to androgens. This supports the hypothesis that androgens act via the dermal papilla and suggests that cultured dermal papilla cells may offer a model system for studying androgen action in androgenetic alopecia.
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Parsons, Agata M., and Gerrit J. Bouma. "A Potential Role and Contribution of Androgens in Placental Development and Pregnancy." Life 11, no. 7 (July 1, 2021): 644. http://dx.doi.org/10.3390/life11070644.
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Successful pregnancy requires the establishment of a highly regulated maternal–fetal environment. This is achieved through the harmonious regulation of steroid hormones, which modulate both maternal and fetal physiology, and are critical for pregnancy maintenance. Defects in steroidogenesis and steroid signaling can lead to pregnancy disorders or even fetal loss. The placenta is a multifunctional, transitory organ which develops at the maternal–fetal interface, and supports fetal development through endocrine signaling, the transport of nutrients and gas exchange. The placenta has the ability to adapt to adverse environments, including hormonal variations, trying to support fetal development. However, if placental function is impaired, or its capacity to adapt is exceeded, fetal development will be compromised. The goal of this review is to explore the relevance of androgens and androgen signaling during pregnancy, specifically in placental development and function. Often considered a mere precursor to placental estrogen synthesis, the placenta in fact secretes androgens throughout pregnancy, and not only contains the androgen steroid nuclear receptor, but also non-genomic membrane receptors for androgens, suggesting a role of androgen signaling in placental function. Moreover, a number of pregnancy disorders, including pre-eclampsia, gestational diabetes, intrauterine growth restriction, and polycystic ovarian syndrome, are associated with abnormal androgen levels and androgen signaling. Understanding the role of androgens in the placenta will provide a greater understanding of the pathophysiology of pregnancy disorders associated with androgen elevation and its consequences.
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Roy, Sambit, Binbin Huang, Niharika Sinha, Jianrong Wang, and Aritro Sen. "Androgens regulate ovarian gene expression by balancing Ezh2-Jmjd3 mediated H3K27me3 dynamics." PLOS Genetics 17, no. 3 (March 30, 2021): e1009483. http://dx.doi.org/10.1371/journal.pgen.1009483.
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Conventionally viewed as male hormone, androgens play a critical role in female fertility. Although androgen receptors (AR) are transcription factors, to date very few direct transcriptional targets of ARs have been identified in the ovary. Using mouse models, this study provides three critical insights about androgen-induced gene regulation in the ovary and its impact on female fertility. First, RNA-sequencing reveals a number of genes and biological processes that were previously not known to be directly regulated by androgens in the ovary. Second, androgens can also influence gene expression by decreasing the tri-methyl mark on lysine 27 of histone3 (H3K27me3), a gene silencing epigenetic mark. ChIP-seq analyses highlight that androgen-induced modulation of H3K27me3 mark within gene bodies, promoters or distal enhancers have a much broader impact on ovarian function than the direct genomic effects of androgens. Third, androgen-induced decrease of H3K27me3 is mediated through (a) inhibiting the expression and activity of Enhancer of Zeste Homologue 2 (EZH2), a histone methyltransferase that promotes tri-methylation of K27 and (b) by inducing the expression of a histone demethylase called Jumonji domain containing protein-3 (JMJD3/KDM6B), responsible for removing the H3K27me3 mark. Androgens through the PI3K/Akt pathway, in a transcription-independent fashion, increase hypoxia-inducible factor 1 alpha (HIF1α) protein levels, which in turn induce JMJD3 expression. Furthermore, proof of concept studies involving in vivo knockdown of Ar in the ovary and ovarian (granulosa) cell-specific Ar knockout mouse model show that ARs regulate the expression of key ovarian genes through modulation of H3K27me3.
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Varlamov, Oleg, Ashley E. White, Julie M. Carroll, Cynthia L. Bethea, Arubala Reddy, Ov Slayden, Robert W. O'Rourke, and Charles T. Roberts. "Androgen Effects on Adipose Tissue Architecture and Function in Nonhuman Primates." Endocrinology 153, no. 7 (April 30, 2012): 3100–3110. http://dx.doi.org/10.1210/en.2011-2111.
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The differential association of hypoandrogenism in men and hyperandrogenism in women with insulin resistance and obesity suggests that androgens may exert sex-specific effects on adipose and other tissues, although the underlying mechanisms remain poorly understood. Moreover, recent studies also suggest that rodents and humans may respond differently to androgen imbalance. To achieve better insight into clinically relevant sex-specific mechanisms of androgen action, we used nonhuman primates to investigate the direct effects of gonadectomy and hormone replacement on white adipose tissue. We also employed a novel ex vivo approach that provides a convenient framework for understanding of adipose tissue physiology under a controlled tissue culture environment. In vivo androgen deprivation of males did not result in overt obesity or insulin resistance but did induce the appearance of very small, multilocular white adipocytes. Testosterone replacement restored normal cell size and a unilocular phenotype and stimulated adipogenic gene transcription and improved insulin sensitivity of male adipose tissue. Ex vivo studies demonstrated sex-specific effects of androgens on adipocyte function. Female adipose tissue treated with androgens displayed elevated basal but reduced insulin-dependent fatty acid uptake. Androgen-stimulated basal uptake was greater in adipose tissue of ovariectomized females than in adipose tissue of intact females and ovariectomized females replaced with estrogen and progesterone in vivo. Collectively, these data demonstrate that androgens are essential for normal adipogenesis in males and can impair essential adipocyte functions in females, thus strengthening the experimental basis for sex-specific effects of androgens in adipose tissue.
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Campo, S., RS Carson, and JK Findlay. "Acute effect of PMSG on ovarian androgen-binding sites in the intact immature female rat." Reproduction, Fertility and Development 4, no. 1 (1992): 55. http://dx.doi.org/10.1071/rd9920055.
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Androgen-binding activity in ovaries containing only immature follicles is compared with that in ovaries stimulated with pregnant mare serum gonadotrophin to induce development of large preovulatory follicles. The androgen-binding sites present in cytosols prepared from unstimulated ovaries exhibited kinetics, affinity and a range of specificities for natural and synthetic androgens consistent with those exhibited by the androgen receptor isolated from androgen-sensitive tissues. Studies of sedimentation and DNA binding suggest that the receptor-like androgen-binding site present in unstimulated ovaries exists as the 'non-activated' form which is able to undergo transformation and bind to nuclear DNA. Properties of the androgen-binding sites isolated from ovaries stimulated with gonadotrophin were very different from those of the androgen receptor present in unstimulated ovaries. Specificity for androgens was reduced, capacity for dihydrotestosterone (DHT) and methyltrienolone (R1881) increased and androgen-binding activity was associated exclusively with the 4.5S form which was not able to bind to nuclear DNA. These data confirm that a shift from a receptor-like to a nonfunctional androgen-binding site is associated with the development of ovulatory follicles and suggest that shifts in androgen-binding populations will determine the response of developing ovarian follicles to androgens.
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Gatson, Joshua W., and Meharvan Singh. "Activation of a Membrane-Associated Androgen Receptor Promotes Cell Death in Primary Cortical Astrocytes." Endocrinology 148, no. 5 (May 1, 2007): 2458–64. http://dx.doi.org/10.1210/en.2006-1443.
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In the central nervous system, androgens can exert either protective or damage-promoting effects. For example, testosterone protects neurons against β-amyloid toxicity, whereas in other studies, testosterone exacerbated stroke-induced lesion size. The mechanism underlying this duality of androgens is still unclear. Recently, our laboratory reported that androgens elicit opposite effects on the ERK/MAPK and Akt signaling pathways, depending on whether a membrane androgen receptor (AR) or intracellular AR was activated. By extension, we hypothesized that androgens may affect cell viability differently depending on which receptor is activated. Here, we found that dihydrotestosterone (DHT) protected primary cortical astrocytes from the metabolic and oxidative insult associated with iodoacetic acid-induced toxicity, whereas DHT-BSA, a cell impermeable analog of DHT that preferentially targets the membrane AR, suppressed Akt signaling, increased caspase 3/7 activity, and enhanced iodoacetic acid-induced cell death. Interestingly, DHT-BSA also blocked the protective effects of DHT and estradiol. Collectively, these data support the existence of two, potentially competing, pathways for androgens in a given cell or tissue that may provide insight into the controversy of whether androgen therapy is beneficial or detrimental.
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Heemers, Hannelore V., Guido Verhoeven, and Johannes V. Swinnen. "Androgen Activation of the Sterol Regulatory Element-Binding Protein Pathway: Current Insights." Molecular Endocrinology 20, no. 10 (October 1, 2006): 2265–77. http://dx.doi.org/10.1210/me.2005-0479.
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Abstract The cellular effects of androgens are mediated by a cognate receptor, the androgen receptor. Typically, the androgen receptor is viewed to exert its activity by binding to androgen response elements located in or near the promoter region of target genes, thereby directly affecting the expression of these genes. However, increasing evidence indicates that androgens may also indirectly influence the expression of genes that do not contain androgen response elements by modulating the activity of secondary transcription factors, mediating the expression of growth factors acting in a paracrine or autocrine fashion, or by inducing changes in the production of other hormones. These indirect effects of androgens can induce cascade-like actions and may play an important role in more complex processes involving coordinated responses of genes, cells, and organs. Previously, our laboratory has identified and characterized a novel indirect mechanism of androgen action involving proteolytical activation of the key lipogenic transcription factor sterol regulatory element-binding protein (SREBP), resulting in the coordinate up-regulation of entire cellular lipogenic pathways. Interestingly, activation of SREBPs by androgens occurs not only under normal physiological conditions but has also been observed in a growing number of pathologies, and more in particular in the setting of steroid-regulated cancers, where increased lipogenesis has been shown to have remarkable diagnostic and prognostic potential and is considered a prime target for novel therapeutic approaches. This review aims to analyze current insights into the molecular mechanism(s) underlying androgen activation of the SREBP pathway and to ascertain the extent to which this phenomenon can be generalized to androgen-responsive cell systems.